It has been estimated that 70% of the bacteria that cause hospital-acquired infections are now resistant to one or more antibiotics (Taubes G (2008) The bacteria fight back. Science 321(5887):356-61). One of the most alarming antibiotic-resistant bacterial species is Staphylococcus aureus. Specifically, methicillin-resistant S. aureus (MRSA) are the group of S. aureus strains resistant to the entire class of β-lactam antibiotics. Hospital-acquired MRSA (HA-MRSA) often leads to severe and life-threatening infections, such as those at surgical sites, in the bloodstream, or pneumonia, while community-acquired MRSA (CA-MRSA) typically leads to superficial skin infections that can ultimately progress to induce severe invasive complications, such as necrotizing fasciitis (Lowy F D (1998) Staphylococcus aureus infections. N Engl J Med 339(8):520-32; Tang Y W & Stratton C W (2010) Staphylococcus aureus: An old pathogen with new weapons. Clin Lab Med 30(1):179-208). In some cases, individuals have died within two days of infection due to the ineffectiveness of present-day antibiotics (Romero-Vivas et al. (1995) Mortality associated with nosocomial bacteremia due to methicillin-resistant Staphylococcus aureus. Clin Infect Dis 21(6):1417-23).
Approval of new antibiotics, including linezolid (oxazolidinone class) in 2000, daptomycin (cyclic lipopeptide class) in 2003, and tigecycline (glycylcycline class) in 2005, provides alternatives to vancomycin, which was formerly the only antibiotic treatment for MRSA (Micek S T (2007) Alternatives to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 45 Suppl 3:S184-90). These new antibiotics, along with increased awareness and adherence to universal decolonization practices, have led to a decrease in the incidence of MRSA in intensive care units (Huang S S et al. (2013) Targeted versus universal decolonization to prevent ICU infection. N Engl J Med 368(24):2255-65). Nonetheless, a recent report from the Centers for Disease Control and Prevention indicates there are still over 80,000 severe MRSA infections per year in the United States, resulting in over 11,000 deaths (e.g., see CDC (2013) Antibiotic resistance threats in the United States, 2013. Centers for Disease Control and Prevention, Atlanta). The same CDC report labeled MRSA as a “serious” public health threat, and vancomycin-resistant S. aureus (VRSA) as a “concerning” threat, underscoring the need for development of alternative therapeutics.
To counteract bacterial resistance and ameliorate the problems caused by S. aureus infections, endolysin therapy is one avenue that is being pursued (Borysowski J et al. (2011) Potential of bacteriophages and their lysins in the treatment of MRSA: current status and future perspectives. BioDrugs 25(6):347-55; Nelson D C et al. (2012) Endolysins as antimicrobials. Adv Virus Res 83:299-365). Endolysins are enzymes released by bacteriophages during the lytic cycle of viral infection. A lytic enzyme is capable of specifically cleaving bonds that are present in the peptidoglycan of bacterial cells to disrupt the bacterial cell wall. The bacterial cell wall peptidoglycan is highly conserved among most bacteria, and cleavage of only a few bonds is believed to disrupt the bacterial cell wall. Once produced within the bacterial cytoplasm by replicating bacteriophage, endolysins hydrolyze bonds in the bacterial cell wall (i.e. peptidoglycan) until lysis is complete.
The idea of utilizing endolysins therapeutically is based on the phenomenon of “lysis from without”, a phrase used to describe the destruction of the bacterial envelope without production of phage virions (Abedon S T (2011) Lysis from without. Bacteriophage 1(1):46-49). This phenomenon only occurs in Gram-positive organisms, such as MRSA, because such bacteria lack an outer membrane protecting the cell wall (Schmelcher et al. (2011) Domain shuffling and module engineering of Listeria phage endolysins for enhanced lytic activity and binding affinity. Microb Biotechnol 4(5):651-62). Rather, the cell wall of such Gram-positive bacteria includes interconnecting layers consisting primarily of peptidoglycan. Gram-positive bacteria include, inter alia, numerous species within the genera Actinomyces, Bacillus, Listeria, Lactococcus, Staphylococcus, Streptococcus, Enterococcus, Mycobacterium, Corynebacterium, and Clostridium. 
The classical structure of endolysins that act on Gram-positive cell walls employs a modular architecture consisting of an N-terminal catalytic domain linked to a C-terminal cell wall binding domain (CBD). The catalytic domain is responsible for cleaving specific covalent bonds in the peptidoglycan structure that are essential for maintaining its intrinsic structural integrity. The CBD confers endolysin specificity by recognizing and noncovalent binding to species- or strain-specific epitopes associated with the cell envelope. It is the high specificity derived by the combined actions of the catalytic and CBD domains that cause endolysins to be highly refractory to the resistance commonly observed upon treatment with classical antibiotics (Fischetti V A (2005) Bacteriophage lytic enzymes: novel anti-infectives. Trends Microbiol 13(10):491-6; Schuch R et al. (2002) A bacteriolytic agent that detects and kills Bacillus anthracis. Nature 418(6900):884-9). This is due to the evolution of bacteriophage to target specific, conserved bonds in the peptidoglycan of a bacteria cell wall, ensuring that the progeny phage will survive (Low L Y et al. (2011) Role of net charge on catalytic domain and influence of cell wall binding domain on bactericidal activity, specificity, and host range of phage lysins. J Biol Chem 286(39):34391-403). However, if resistance were to develop, endolysins could be engineered through domain shuffling or used in combination with other endolysins or antibiotics to prolong the use of these enzymes (Shen Y et al. (2012) Phage-based Enzybiotics. In: Abedon S, Hyman P (eds) Bacteriophages in Health and Disease. CABI Press, pp 217-239).
Thus, identified endolysins have been shown to be effective in killing specific bacterial strains. However, there still exists a need for additional and/or alternative endolysin-based therapeutics, particularly therapeutics exhibiting superior activity and/or which target other bacterial strains as compared to known therapeutics.